Development of a minimal saponin vaccine adjuvant based on QS-21 (original) (raw)

Nature Chemistry volume 6, pages 635–643 (2014)Cite this article

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Abstract

Adjuvants are materials added to vaccines to enhance the immunological response to an antigen. QS-21 is a natural product adjuvant under investigation in numerous vaccine clinical trials, but its use is constrained by scarcity, toxicity, instability and an enigmatic molecular mechanism of action. Herein we describe the development of a minimal QS-21 analogue that decouples adjuvant activity from toxicity and provides a powerful platform for mechanistic investigations. We found that the entire branched trisaccharide domain of QS-21 is dispensable for adjuvant activity and that the C4-aldehyde substituent, previously proposed to bind covalently to an unknown cellular target, is also not required. Biodistribution studies revealed that active adjuvants were retained preferentially at the injection site and the nearest draining lymph nodes compared with the attenuated variants. Overall, these studies have yielded critical insights into saponin structure–function relationships, provided practical synthetic access to non-toxic adjuvants, and established a platform for detailed mechanistic studies.

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Acknowledgements

Dedicated to the memory of our mentor and colleague, David Y. Gin (1967–2011). We thank S. J. Danishefsky, M. M. Adams and W. E. Walkowicz for helpful discussions, G. Sukenick, H. Liu, H. Fang and S. Rusli for expert NMR and mass spectral support and K. K. Sevak, N. Ramos and C. B. Davis for technical support with biodistribution and radiometric studies. Generous financial support was provided by the European Commission (Marie Curie International Outgoing Fellowship to A.F-T.), the National Institutes of Health (R01 AI085622 to J.S.L. and D.Y.G., R01 GM058833 to D.S.T. and D.Y.G., CCSG P30 CA008748 in support of the Center of Comparative Medicine and Pathology and the Radiochemistry and Molecular Imaging Probe Core), William and Alice Goodwin and the Commonwealth Foundation for Cancer Research and the Experimental Therapeutics Center of MSKCC.

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Author notes

  1. Philip O. Livingston
    Present address: Present address: Adjuvance Technologies Inc., 116 West 22nd St, Suite No. 1, New York 10011, USA.,
  2. David Y. Gin: Deceased

Authors and Affiliations

  1. Molecular Pharmacology & Chemistry Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, 10065, USA
    Alberto Fernández-Tejada, Jeffrey R. Gardner, Derek S. Tan & David Y. Gin
  2. Pharmacology Program, Weill Cornell Graduate School of Medical Sciences, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, 10065, USA
    Eric K. Chea, Derek S. Tan & David Y. Gin
  3. Department of Medicine, Melanoma & Immunotherapeutics Service, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, 10065, USA
    Constantine George, Philip O. Livingston & Govind Ragupathi
  4. Department of Radiology, Radiochemistry & Imaging Science Service, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, 10065, USA
    NagaVaraKishore Pillarsetty & Jason S. Lewis
  5. Tri-Institutional Research Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, 10065, USA
    Derek S. Tan & David Y. Gin

Authors

  1. Alberto Fernández-Tejada
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  2. Eric K. Chea
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  3. Constantine George
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  4. NagaVaraKishore Pillarsetty
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  5. Jeffrey R. Gardner
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  6. Philip O. Livingston
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  7. Govind Ragupathi
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  8. Jason S. Lewis
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  9. Derek S. Tan
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  10. David Y. Gin
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Contributions

A.F-T., E.K.C., N.P., J.R.G., G.R., J.S.L., D.S.T. and D.Y.G. conceived and designed the experiments. A.F-T. and E.K.C. performed the syntheses. C.G. performed the preclinical mouse-vaccination experiments. C.G. and N.P. performed the biodistribution experiments. J.R.G. performed the fluorescence imaging experiments. A.F-T., E.K.C., N.P., J.R.G., P.O.L., G.R., J.S.L., D.S.T. and D.Y.G. analysed the data. A.F-T. and D.S.T. wrote the manuscript.

Corresponding authors

Correspondence toGovind Ragupathi, Jason S. Lewis or Derek S. Tan.

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Competing interests

J.R.G., P.O.L., G.R. and D.Y.G are founders of Adjuvance Technologies Inc. and have financial interests in the company.

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Fernández-Tejada, A., Chea, E., George, C. et al. Development of a minimal saponin vaccine adjuvant based on QS-21.Nature Chem 6, 635–643 (2014). https://doi.org/10.1038/nchem.1963

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